This invention relates generally to the field of pyridine chemistry with particular application in providing improved electrochemical processes for the reduction of pyridine carboxamide bases in commercially practicable flow cells. In this regard, this invention constitutes an improvement and continuation of applicant's earlier work as described and claimed in his prior patent application, Ser. No. 597,013 filed Apr. 5, 1984 and entitled Electrochemical Reductions of Cyanopyridine Bases, which has since issued as U.S. Pat. No. 4,482,437 on Nov. 13, 1984.
Much attention has focused over the years on the reduction of carboxamides in general, which are organic compounds containing the radical "--CONR.sup.1 R.sup.2 " to their corresponding amines or alcohols. The field of pyridine chemistry has been no less attentive than others in this regard, with the products of such reduced pyridine carboxamides exhibiting valuable uses in such applications as pharmaceutical products, carbon dioxide scavengers, corrosion inhibitors, chelating agents, and others.
Historically, three approaches have been used to reduce these carboxamides to their corresponding alcohols or amines, those being catalytic hydrogenation, chemical reduction, and electrochemical reduction. In this regard, the ideal approach would be one that selectively produced high yields of alcohol or amine using an inexpensive reducing agent, low temperatures, and not involving heavy demands on, or uses of, pollution control procedures. Reported successes approaching this ideal have been few. For instance, reported catalytic hydrogenations of carboxamides using rhenium catalysts usually produced the amine, but undesirable side reactions occurred (H. S. Broadbent, G. C. Campbell, W. J. Bartley, and J. H. Johnson, J. Org. Chem. 24, 1847 (1959)). High temperature and pressure were required and N-dealkylation was a major reaction pathway in some cases. Scrambling of different N-alkyl groups was also a problem (M. Sekiya and K. Ito, Chem. Pharm. Bull. (Japan) 14, 996 (1966); M. Sekiya and M. Tomie, ibid. 15, 238 (1697)).
Birch reduction of carboxamides was a general technique only for secondary or tertiary carboxamides and produced the aldehyde, not the amine or alcohol (A. J. Birch and H. Smith, Quart. Rev. (London) 12, 17 (1958)).
Metal hydride reducing agents have produced a variety of products, sometimes resulting from dehydration of the primary carboxamide to give a nitrile (M. S. Newman and T. Fukunaga, J. Amer. Chem. Soc. 82, 693 (1960); S. E. Ellzey, C. H. Mack, and W. J. Connick, J. Org. Chem. 32, 846 (1967)). Occasionally, the acyl carbon-nitrogen bond was cleaved (N. G. Gaylord, "Reduction with Complex Metal Hydrides," Interscience Publishers, New York, 1956, pp. 544-594). Aldehydes were also produced when hydrides were used. Primary carboxamides reacted sluggishly and one equivalent of active hydride was consumed for each proton on nitrogen. These factors in addition to both the high cost of hydride reagents and their difficulty in handling made this methodology unsuitable for industrial processes. Furthermore, the strongly basic nature of hydrides initiated unwanted side reactions which were a further complicating factor.
With regard to the production of pyridyl carbinols, the carboxamide functionality was not used as a starting material except during electrolytic reduction. For instance, the pyridine carbonitriles were reduced catalytically used Pd on carbon catalyst and aqueous hydrochloride acid (U.S. Pat. No. 2,615,896). The pyridine carboxylic esters were also reduced to the carbinols using hydride reagents (British Pat. No. 631,078); and the pyridine carboxylic acids were reduced with zinc in acetic acid (F. Sorm and L. Sedivy, Coll. Czech. Chem. Commun. 13, 289 (1948)). Each of these reductions suffered from one or more of the following disadvantages: use of corrosive reagents, high temperatures, expensive reagents, or being applicable only in special restricted cases or circumstances.
Electrochemical procedures fulfill many of the desired features of an ideal carboxamide reduction since low temperatures can be used, the electron is an inexpensive reducing agent, the technology is generally applicable, selectivity can be achieved, and such methods normally do not place high demands on pollution controls. In the case of pyridine carboxamides, there have been some analytical studies, particularly of the three isomeric monocarboxamides (V. A. Serozetdinova, B. V. Suvorov, and O. A. Songina, Khim. Geterotsikl. Soedin. 1973, 327; D. Therenot and R. Buret, J. Electroanal. Chem. Interfacial Electrochem., 40, 197 (1972); C. O. Schmakel, K. S. V. Santhanam and P. J. Elving, J. Electrochem. Soc. 121, 345 (1974)). However, these analytical procedures were unsuitable for producing more than milligram quantities of products and, in some cases, even the identity or quantity of products formed were unknown.
The need for selectivity is a key criteria in determining the utility of electrochemical technology since there are six possible major reduction products obtainable from a carboxamide reduction by five reaction pathways. Moreover, additional products can be formed from these initial six major ones either by chemical reaction, for instance, of the radical anion shown in pathway I, or by further reduction processes, for instance, of the aldehyde shown in pathway III. Graphically, these can be depicted as follows for three given radicals R.sup.1, R.sup.2 and R.sup.3 : ##STR1##
The reduction of carboxamides to amines (pathways III, IV, V) has been the most extensively studied of these reactions. The other two (I, II) are simply alternate pathways that the reaction can proceed through, the first (I) having shown only efficacy with nicotinamides while the second (II) involving products which are not usually stable on isolation.
Besides these five pathways, further reduction of the products, or alternative pathways altogether, have been reported for pyridine carboxamides. For example, the product alcohol or amine was reductively cleaved to the corresponding picoline; in addition, pyridine ring reduction took place at all stages to form a muiltitude of pyridine and reduced-pyridine products (F. Sorm., Coll. Czech. Chem. Comm., 13, 57 (1948); J. P. Wibault and H. Boer, Rec. Trav. Chim., 68, 72 (1949); M. Ferles and M. Pyrstas, Coll. Czech. Chem. Commun., 24, 3326 (1959); M. Ferles and A. Tesarova, ibid., 32, 1631 (1967)). A study by Iversen reported in Acta. Chem. Scand. 24, 2459 (1970) explored the possible electrochemical reduction of picolinamide and isonicotinamide to the corresponding aldehydes. However, there was no attempt to investigate the utility of this reaction past the aldehyde stage. In addition, the Iversen reductions were done at a mercury cathode which is unsuitable for industrial use due to the toxic nature and strict environmental regulation of mercury. Aqueous hydrochloric acid was used as the electrolyte and due to the noxious and corrosive nature of HCl, this should be avoided for industrial utility. Still further, the aldehydes Iverson produced were shown to preferentially dimerize on further electrochemical reduction which significantly limits the selectivity of such processes to form carbinol products (pathway IV) which proceed through this aldehyde stage (J. F. Rusling and P. Zuman, J. Org. Chem., 46, 1906 (1981)).
Three other reports of electrochemical reduction of pyridine carboxamides are known. The report by Nonaka, et al., Electrochim. Acta. 26, 887 (1981) described a technology that uses a mercury cathode which was not suitable for industrial use for the reasons mentioned above. Two reports by H. Lund (Acta Chem. Scand. 17, 2325 (1963) and Abhandl. Deut. Akad. Wiss. Berlin Kl. Chem., Geol., Biol. 1, 434 (1964)) explored the carboxamide reductions using a controlled junction potential at a mercury cathode and using aqueous hydrochloric acid electrolyte or acetic and citric acid buffers. Besides the same impracticality of these cathode and electrolyte materials. Lund's product distribution was pH dependent. In strong acid, below pH.perspectiveto.3.5, the major product of isonicotinamide reduction was reported to be the aldehyde (pathway III). If the reduction continued in strong acid past the aldehyde stage, the carbinol became the major product in a reported 53% yield. Up to 2 Faradays per mole of charge passed, however, the aldehyde was the sole product. In weak acid, above pH.perspectiveto.3.5, no aldehyde was apparently formed even at intermediate stages of the reduction and the major product was reported to be the carbinol (pathway IV). In contrast, the tertiary carboxamide, N-phenyl-N-methyl-isonicotinamide, gave no aldehyde on reduction even at low pH. The secondary carboxamide, N-phenylisonicotinamide, also gave no aldehyde even at low pH.
Thus, in Lund's work, the reported selectivity of product formation was not good, except in weak acid media which suppressed the amine formation. Even then the yield was not high. This work also required using a power supply (potentiostat) that controlled the cathode junction potential. This is impractical for commercial syntheses as such potentiostats are only useful in a laboratory environment. In contrast, power supplies which control the output current or output voltage are used in commercial applications, as are uncontrolled power supplies. However, the use of such a controlled-current power supply in place of the potentiostat resulted in worse product mixtures and reportedly reduced selectivity even further (H. Lund, Adv. Heterocycl. Chem. 12, 305 (1970)).
In addition to the points discussed above, all literature and patent references known to the applicant which have explored such electrochemical means at all have made use of rudimentary beaker cell technology which has little or no commercial significance. Although these beaker cells are acceptable for small-scale syntheses and analytical experiments, they have little economic value and are not preferred cell types for a commercial setting. There is no teaching or suggestion in any reference to applicant's knowledge that such electrochemical reductions of pyridine carboxamide bases have been or can be performed or even attempted, using other cell geometries and techniques which may have commercial importance.